title: Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells.
abstract: TG-interacting factor 1 (TGIF1) is a transcriptional repressor that can modulate retinoic acid and transforming growth factor β signaling pathways. It is required for myeloid progenitor cell differentiation and survival, and mutations in the TGIF1 gene cause holoprosencephaly. Furthermore, we have previously observed that acute myelogenous leukemia (AML) patients with low TGIF1 levels had worse prognoses. Here, we explored the role of Tgif1 in murine hematopoietic stem cell (HSC) function. CFU assays showed that Tgif1(-/-) bone marrow cells produced more total colonies and had higher serial CFU potential. These effects were also observed in vivo, where Tgif1(-/-) bone marrow cells had higher repopulation potential in short- and long-term competitive repopulation assays than wild-type cells. Serial transplantation and replating studies showed that Tgif1(-/-) HSCs exhibited greater self-renewal and were less proliferative and more quiescent than wild-type cells, suggesting that Tgif1 is required for stem cells to enter the cell cycle. Furthermore, HSCs from Tgif1(+/-) mice had a phenotype similar to that of HSCs from Tgif1(-/-) mice, while bone marrow cells with overexpressing Tgif1 showed increased proliferation and lower survival in long-term transplant studies. Taken together, our data suggest that Tgif1 suppresses stem cell self-renewal and provide clues as to how reduced expression of TGIF1 may contribute to poor long-term survival in patients with AML.
authors.affiliation: Departments of Pediatrics.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Bethany
authors.initials: B
authors.lastname: Womack
authors.forename: David
authors.initials: D
authors.lastname: Wotton
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Utpal
authors.initials: U
authors.lastname: Davé
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Scott
authors.initials: S
authors.lastname: Hiebert
authors.forename: Stephen
authors.initials: S
authors.lastname: Brandt
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C490797:Tgif1 protein, mouse